Staphylococcus aureus is the most common cause of nosocomial infections. Staphylococcal isolates resistant to every clinically useful antibiotic except vancomycin exist in virtually every hospital. A report of an S. aureus isolate with reduced vancomycin susceptibility (VIRSA) introduces the possibility of lethal infections, such as bacteremia and infective endocarditis, for which there is no effective chemotherapy. The investigator's overall goal is to develop recombinant lysostaphin as a therapeutic agent for staphylococcal endocarditis. A staphylolytic enzyme, lysostaphin was studied in the 1960s and 1970s but abandoned due to fears about potential immunological consequences and because numerous other agents were then available. Our recent results in the rabbit endocarditis model, in which lysostaphin significantly outperformed vancomycin, suggest that development of lysostaphin as a therapeutic agent is worth revisiting. Phase I goals are to establish the efficacy and potential immunogenicity of lysostaphin used alone and in combination with other antibiotics, through in vitro and in vivo studies including rabbit models of aortic valve endocarditis and serum sickness. Second, we will implement improvements to AMBI's current fermentation, purification, and analytical technology, such that 3-4 kg of lysostaphin can be produced at the beginning of Phase II, for toxicology and Phase I human clinical trials. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE